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30 Years of Finding Answers in the Lost Pines

Conquest -
Fall 2007

By Scott Merville

Immersed in the environmental awakening of the 1960s and 1970s, M. D. Anderson’s first president, R. Lee Clark, M.D., pursued a dynamic vision to build a research park in the Lost Pines region of Central Texas, modeling it after North Carolina’s Research Triangle Park.

In an arc from San Antonio to Austin to Houston to Galveston, Texas research institutions would build a world-class presence in environmental science and ecology, studying the effects of environmental factors on cancer and other major diseases.

Clark worked with the Texas Department of Parks and Wildlife, the City of Smithville, Bastrop County and the Texas Legislature to transfer 717 acres of land in Buescher State Park, 40 miles southeast of Austin, to The University of Texas to house the research park.

While other institutions bowed out of the plan in those less collaborative times, M. D. Anderson stayed and thrived. Since 1977, M. D. Anderson’s Science Park-Research Division at the Virginia Harris Cockrell Cancer Research Center in Smithville, Texas, has earned international recognition from its unique rural location, camped scientifically at the tangled crossroads where the varied pathways that lead to cancer meet.

Scientists at the Cockrell Cancer Research Center have made significant contributions over the past 30 years, including establishing the first direct link between a chemical carcinogen in tobacco smoke and human lung cancer, discovering a cellular receptor that plays a crucial role in regulating the immune system and identifying a tumor-suppressor gene involved in melanoma susceptibility.

Expanding scope

Understanding carcinogenesis — the birth of cancer cells — is the facility’s core expertise, but in its 30th year, a major grant renewal expands the scope of its research to other diseases and cultivates institutional collaboration in the spirit of Clark’s vision.

“It takes a broad multidisciplinary approach to understand how genes interact with environmental factors to cause cancer,” according to John DiGiovanni, Ph.D., director of the Cockrell Cancer Research Center and chair of M. D. Anderson’s Department of Carcinogenesis. “One long-term goal of our research is to identify genetic characteristics that pose a high risk for development of cancer due to environmental exposures. Then, we want to offset that increased risk by, for example, altering a person’s diet or developing novel chemopreventive strategies.”

Xuetong Shen, Ph.D., and his colleagues found that two molecular pathways work together to protect cells against DNA damage and may provide new targets for attacking cancer.

The five-year, $8.3 million renewal grant from the National Institute for Environmental Health Sciences came as the Cockrell Cancer Research Center celebrated three decades of detecting the origins of cancer at its labs in Central Texas. The grant continues funding of the 10-year-old Center for Research on Environmental Disease, one of only 23 centers in the nation exploring environmental causes of disease.

The word “environmental” often conjures up images of air and water pollution, and toxic chemicals in workplaces and neighborhoods. To those factors, scientists also add natural carcinogens, such as ultraviolet light from the sun and behavioral factors, such as diet and use of tobacco and alcohol. Other conditions, such as obesity, are separate risk factors for cancer, heart disease and diabetes.

“This center is very broad in its approach,” DiGiovanni says. “We study everything from the molecular mechanisms of how environmental agents cause toxicity and induce cancer to how diet affects our responses to environmental exposures to the interactions between genes and these external factors.”

A new feature of the center is a greater focus on translational research, he adds. Translational research is the bridge between basic science research that discovers fundamental molecular aspects of disease and clinical research that carefully tests new prevention and therapeutic strategies in patients.

Most of the center’s work is in preclinical translational research, the testing of lab findings in animal models. Collaboration with M. D. Anderson’s Department of Epidemiology and a new connection to The University of Texas School of Public Health at Houston provide ties to population research.

Clinical associations include participation in three M. D. Anderson Specialized Programs of Research Excellence grants in prostate, gynecologic, and head and neck cancers. SPORE programs are a National Cancer Institute initiative to encourage more efficient translation of laboratory findings to the clinic.

The UT School of Public Health adds expertise in monitoring an individual’s personal exposure to airborne toxins and carcinogens. “This will bring a new research focus on air pollution and human health. Our colleagues focus on asthma and cardiovascular disease, so this will clearly broaden the scope of environmental diseases under study at the center,” DiGiovanni says.

The grant also includes the Center for Molecular and Cellular Toxicology, a joint interdisciplinary center with The University of Texas at Austin that conducts basic toxicology research.

While the grant renewal expands translational research and encompasses new categories of disease, scientists at the Cockrell Cancer Research Center continue to make important discoveries.

Two meaningful examples come from Assistant Professor Yinling Hu, Ph.D., and Associate Professor Xuetong “Snow” Shen, Ph.D., who recently published their findings in major journals.

Silencing a cancer defense

Cells divide to multiply. As a cell splits into two identical versions of its former self, the process is halted temporarily by checkpoint genes, which allow the dividing cell to be analyzed for genetic damage. Normally, genetic errors found at the checkpoints are either repaired by specialized cellular machinery, or the cell is forced to kill itself to prevent the damage from spreading.

Hu found that a protein largely absent in one type of skin cancer normally protects an important checkpoint gene from being chemically turned off.

Restoring the expression of the missing protein, called IKK, also restored the checkpoint gene, which had been silenced by a chemical process known as methylation. Methyl groups, consisting of a carbon atom surrounded by three hydrogen atoms, attach to specific locations on a gene and prevent the gene from expressing its protein.

“DNA methylation is largely responsible for shutting down the checkpoint gene expression in human cancer cells,” Hu explains. “Our finding opens a new avenue for identifying new therapeutic targets for battling cancer. Those targets may be used to prevent silencing of the gene in cancer cells and allow us to eliminate those cells.”

Yinling Hu, Ph.D., and her team discovered that the absence or weak expression of a specific protein found in skin cancer results in genetic instability and disease development.

Published in the journal Molecular Cell, the paper by Hu, lead author Feng Zhu, Ph.D., and colleagues focused on aggressive squamous cell carcinomas. However, the checkpoint gene is silenced in a variety of other human epithelial cancers. Epithelial cells make up the outer layers of skin and the inner linings of many organs, including the lungs and the gastrointestinal, reproductive and urinary tracts.

It’s all in the packaging

It’s easy to think of genes neatly lined up on our 23 chromosomes, carefully spelled out in various combinations of the four bases that are the building blocks of DNA.

Not quite, Shen says.

DNA is tightly intertwined with proteins known as histones and assembled in histone/DNA units called nucleosomes along the connecting length of a string of DNA. “This structure is often referred to as beads on a string,” he says, and is collectively known as chromatin.

So it’s not just about genes, it’s also about how they are, in effect, packaged.

“Chromatin creates barriers to DNA against anything that wants access to DNA,” he explains. “Chromatin remodeling shuffles the nucleosomes around to create access to DNA. This moving and sliding of the ‘beads on the string’ is accomplished by large protein complexes.”

In the journal Cell, Shen and colleagues describe how a chromatin remodeling complex he discovered connects with a damage control pathway to contain DNA wreckage.

When genetic damage occurs, a group of signaling proteins regulate the checkpoint and repair pathways by attaching phosphate groups (chemical compounds) to other proteins involved in damage control.

“We found that one of the proteins that gets the phosphate groups was a subunit of a chromatin remodeling complex, and apparently the cell uses this event to regulate DNA damage response,” Shen says. “This connection between a signaling pathway crucial to DNA damage control and a chromatin remodeling pathway opens an entirely new category of targets for potentially attacking cancer.”

Discoveries to be continued

The molecular story of cancer’s origins has progressed from genetic mutation to genetic damage to specific checkpoint and repair pathways to the nuances of chromatin.

As the tale grows more complicated, Smithville scientists dig ever deeper into the details.

Along the way, they know they can count on the surrounding community.

“Local support has always been a wonderful aspect of the Cockrell Cancer Research Center,” DiGiovanni notes. “Friends of the Science Park provide moral support and financial help for us. We greatly appreciate their efforts.”

About $45,000 in proceeds from the anniversary celebration and related events will fund carcinogenesis research.

Science in the Community

Robin Fuchs-Young, Ph.D., and the staff of the Community Outreach andEducation Program want everyone to appreciate the benefits of biomedical research and to learn how to prevent environmental disease, especially cancer.

A grant from the prestigious Howard Hughes Medical Institute may help them do that sooner than later. The five-year, $750,000 award funds a comprehensive project to enhance science and health education in Smithville, Texas, schools and to promote community interest in science and biomedical research.

From her lab in Smithville, Texas, Robin Fuchs-Young, Ph.D., is bringing science and biomedical research to area schools and the community.

“Our future scientists are in the classroom right now. It’s vital that we expose them to the importance of science and the many opportunities for scientific and research careers,” says Fuchs-Young, director of COEP at M. D. Anderson’s Science Park-Research Division at the Virginia Harris Cockrell Cancer Research Center in Smithville.

Fuchs-Young and the COEP have a tradition of educational outreach that underpins the Howard Hughes grant, the first awarded to M. D. Anderson.

The Howard Hughes project, known as CENTIPEDe, which stands for Community Education Networks to Integrate Prevention of Environmental Disease, will tailor health and science educational programs to the specific needs of Smithville schools and the community.

CENTIPEDe will provide increased access to science for students through onsite field experiences, hands-on classroom activities, research internships and mentoring opportunities.

For elementary, junior high and high school teachers, there will be workshops and professional development sessions with center faculty and staff, as well as assistance with lesson plans, summer fellowships and activities that provide a “real world” context.

Graduate and post-doctoral trainees who have chosen science for their life’s work will have increased opportunities for career development, including teaching and mentoring students.

CENTIPEDe also will support community programs to enhance scientific literacy and acquaint parents and other Smithville residents with research discoveries and important health information.

Research by national education organizations shows that rural communities have special challenges with science education, according to Fuchs-Young. Students in a rural setting often have limited access to educational resources at school, home and within the community.

The project is a collaborative effort between the Cockrell Cancer Research Center and the Smithville community to develop educational resources and opportunities and to provide these programs to rural communities and educators at the local, state and national level.